rs587781056

Variant names:

• chr16-15724796-G-A
• rs12907
• NM_002474.3:c.3967C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-15724796-G-A
• chrNT_187607.1-1382807-G-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002474.3(MYH11):​c.3967C>T​(p.Leu1323Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0291 in 1,613,774 control chromosomes in the GnomAD database, including 2,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1323L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.085 (1387 hom., cov: 32)
  • Exomes 𝑓: 0.023 (1430 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 5.90
• Publications: 9 publications found

Genes affected

MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 16-15724796-G-A is Benign according to our data. Variant chr16-15724796-G-A is described in ClinVar as Benign. ClinVar VariationId is 138338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.3967C>T	p.Leu1323Leu	synonymous	Exon 30 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.3988C>T	p.Leu1330Leu	synonymous	Exon 31 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.*545G>A		3_prime_UTR	Exon 9 of 9	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.3967C>T	p.Leu1323Leu	synonymous	Exon 30 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.3988C>T	p.Leu1330Leu	synonymous	Exon 31 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.3988C>T	p.Leu1330Leu	synonymous	Exon 31 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12856 AN: 152060 Hom.: 1387 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0593

GnomAD2 exomes AF: 0.0358 AC: 8994 AN: 251106 AF XY: 0.0320

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.0278

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0233 AC: 34107 AN: 1461596 Hom.: 1430 Cov.: 34 AF XY: 0.0229 AC XY: 16657 AN XY: 727132

African (AFR) AF: 0.260 AC: 8712 AN: 33480

American (AMR) AF: 0.0227 AC: 1013 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 559 AN: 26136

East Asian (EAS) AF: 0.0345 AC: 1368 AN: 39700

South Asian (SAS) AF: 0.0270 AC: 2332 AN: 86258

European-Finnish (FIN) AF: 0.0284 AC: 1511 AN: 53138

Middle Eastern (MID) AF: 0.0385 AC: 222 AN: 5768

European-Non Finnish (NFE) AF: 0.0147 AC: 16311 AN: 1112002

Other (OTH) AF: 0.0344 AC: 2079 AN: 60392

GnomAD4 genome AF: 0.0847 AC: 12883 AN: 152178 Hom.: 1387 Cov.: 32 AF XY: 0.0839 AC XY: 6242 AN XY: 74410

African (AFR) AF: 0.252 AC: 10473 AN: 41486

American (AMR) AF: 0.0368 AC: 563 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.0346 AC: 179 AN: 5168

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4824

European-Finnish (FIN) AF: 0.0330 AC: 350 AN: 10608

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0149 AC: 1015 AN: 68018

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0345 Hom.: 524

Bravo AF: 0.0921

Asia WGS AF: 0.0400 AC: 139 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	Aortic aneurysm, familial thoracic 4 (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lissencephaly 4 (1)
-	-	1	Lissencephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=27/73	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12907; hg19: chr16-15818653; COSMIC: COSV55546779; COSMIC: COSV55546779;